The proinflammatory cytokine interleukin-1 (IL-1) elicits a wide array of biological activities that initiate and promote the host response to pathophysiological states including infection, fever, sleep, loss of appetite, acute phase protein synthesis, chemokine production, adhesion molecule upregulation, vasodilation, the coagulant state, increased hematopoiesis, and production and release of matrix metalloproteinases and growth factors. Until recently IL-1 activity was thought to reside in each of two molecules, IL-1 alpha (IL-1α) and IL-1 beta (IL-1β), which are potent inflammatory cytokines that play important roles in host immune responses and in the development of inflammatory and autoimmune diseases. While only being about 25% identical, the two cytokines interact with and activate the same receptor complex, composed of the IL-1 Type-I receptor (IL-1RI) and IL-1 Receptor Accessory Protein (IL-1RAP) subunits. Upon binding and receptor activation, a number of signal transduction pathways are activated including that controlled by NF-kappa B. In fact, IL-1α and IL-1β are thought to positively or negatively modulate NF-kB and AP-1 signaling stimulated through IL-1RI-associated kinase/TNF receptor-associated factor-like complexes recruited through the IL-1 receptor family. IL-1 induces expression of a large number of genes including cytokines, growth factors, cell adhesion molecules transcription factors and proteases. In addition to the agonist peptides, a third IL-1, IL-1 receptor antagonist protein (IL-1RA) can bind to IL-1 receptors and block activity of IL-1α and IL-1β. The IL-1 system has been shown to effect a number of inflammatory diseases in animals and in humans. Blockade of IL-1 signalling with an antibody to either of IL-1α, IL-1βor the IL-1RI blocks the development of the disease processes in animal models of arthritis, encephalitis, contact sensitivity, graft rejection, endotoxic shock and inflammatory bowel disease among others. In addition, the recombinant IL-1 receptor antagonist protein has been shown to block the progression of rheumatoid arthritis in human clinical trials.
Recent studies have shown the IL-1 system is represented by a family of related genes. One IL-1 related gene is IL-18. This cytokine was originally cloned by its ability to induce gamma interferon expression. It was later shown that this molecule had significant structural homology to IL-1 and subsequently shown to bind to receptors highly related, but distinct from the IL-1RI and IL-1RAP. Another member of the family, the IL-1 receptor antagonist (IL-1RA), also binds to IL-1RI but fails to induce the subsequent interaction with IL-1RAP, thus not only not signaling itself, but also, by blocking the receptor, preventing the action of agonist IL-1s. Recently, 4 new IL-1 related molecules have been identified. These proteins share between 13 and 50% identify to the characterized IL-1 molecules. In this respect, two reports have identified overlapping but nonidentical sets of IL-1 related genes including IL-1H1, IL-1H2, IL-1H3 and IL-H4 (Kumar et al., J. Biol. Chem. 275 (2000), 10308–10314), and FILδ, FILε, FILν and FILζ (Smith et al., J. Biol. Chem. 275 (2000),1169–1175). Several of these genes are either identical or clearly derived from the same gene including IL-1H2 and FILν, IL-1H3 and FILδ, and IL-1H4 and FILζ. IL-1H4 and FILζ are 88% identical with changes only at the extreme ends of cDNAs. Thus, these two sequences are derived from alternative splicing of the same gene. Interestingly, most of these molecules are relatively more related to IL-1 RA than to either IL-1α, IL-1β or IL-18, implying that common, IL-1 antagonizing, effect of these molecules may coincide with separate, unique activities. Importantly, while related at the amino acid level, none of the IL-1 related proteins appears to bind to the known IL-1 receptors.